Investigating aspects of the liver-kidney interaction in chronic kidney disease

Abstract

In normal health the liver and kidneys interact with each other harmoniously to maintain a physiological balance. Abnormalities in liver function affect the kidneys and vice versa. There is mounting evidence that more widely prevalent conditions, notably non-alcoholic fatty liver disease (NAFLD), can add to the overall disease burden of chronic kidney disease (CKD) patients. NAFLD is a condition characterised by the accumulation of fat in the liver of people who take minimal or no alcohol. NAFLD is the most common chronic liver disease in Western countries. Several studies have shown NAFLD as a risk factor for CKD and cardiovascular disease outcomes, but such studies have been challenging and scarce in patients with advanced CKD. Fatty liver disease can have additional very serious consequences as it can progress to non-alcoholic steato-hepatitis (NASH), cirrhosis and hepatocellular carcinoma. Currently research is focussing on the influence of uraemic toxins, generated in CKD, on liver physiology, especially hepatic drug metabolising enzymes. CKD affects the elimination of drugs excreted not only by a renal route but also through non-renal routes (bile, gut) and through metabolism (liver). Thus, the clearance of drugs eliminated predominantly by hepatic drug metabolism is altered in CKD. Pharmacokinetic (PK) modelling is being increasingly used for guiding precision drug dosing in in-vitro (wet lab) studies and pharmaceutical research. PK models can be indispensable tools particularly in special populations like CKD, as phase 3 studies usually exclude patients with reduced renal function. There is a call for more research to validate the application of PK models in clinical settings. This research project investigated three salient aspects of the liver-kidney interaction in CKD. I first investigated the association of NAFLD with outcomes in Salford Kidney Study (SKS) patients (a non-dialysis, CKD 3-5 cohort). NAFLD showed a strong and independent association with cardiovascular outcomes, but its presence did not have an impact either on all-cause mortality or CKD progression in our cohort. The implication is that routine screening for NAFLD may be warranted in CKD populations to enable targeted interventions for cardiovascular disease prevention in higher risk patients. To investigate the distribution and association of hepatocellular carcinoma with outcomes, I investigated all cancers in the SKS cohort. Baseline cancer status proved to be an independent risk factor for all-cause mortality but not for renal progression. Cardiovascular disease was noted to be the leading cause of death even in patients with cancer, suggesting the need for a case by case assessment in planning renal replacement therapy options. The third major component of the thesis explored the impact of CKD on the non-renal clearance of hepatically-metabolised drugs by using pharmacokinetic models with tacrolimus in transplant patients and citolopram in CKD patients. Our investigation demonstrated a decline in the hepatic clearance of both tacrolimus and citalopram with worsening CKD, possibly due to the suppression of the hepatic drug metabolising enzymes by the uraemic toxins. These three investigations have unearthed some significant liver-kidney interactions that can help to risk stratify CKD patients and which underpin the need for future research.

Date of Award	1 Aug 2020
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Philip Kalra (Supervisor) & Amin Rostami-Hochaghan (Supervisor)